Effects of Sarcolemmal Background Ca2+ Entry and Sarcoplasmic Ca2+ Leak Currents on Electrophysiology and Ca2+ Transients in Human Ventricular Cardiomyocytes: A Computational Comparison

FIGURE 1. Diagram of Ca2+ handling components in human ventricular myocyte model (Grandi et al., 2010). In this mathematical model, the cytosol is divided into junction, sub-sarcolemmal and bulk compartments. Ca2+ currents through the sarcolemma enter both the junctional and sub-sarcolemmal compartments before diffusing to the bulk cytosol.

FIGURE 2. Effects of modulating the background Ca2+ entry current, ICabk, on Vm, [Ca2+]i, and [Ca2+]SR. (A) Example action potentials for 50% and 200% Gbkg at 1 Hz pacing. Sensitivity analyses of modulating Gbkg on measurements of (B) resting Vm, (C) maximum Vm, and (D) time to 90% repolarization at 1, 2 and 3 Hz pacing. (E) Example [Ca2+]i transients for 50% and 200% Gbkg at 1 Hz pacing. Sensitivity analyses of modulating Gbkg on measurements of (F) diastolic [Ca2+]i, (G) systolic [Ca2+]i, and (H) [Ca2+]i amplitude at 1, 2 and 3 Hz pacing. (I) Example [Ca2+]SR transients for 50% and 200% Gbkg at 1 Hz pacing. Sensitivity analyses of modulating Gbkg on measurements of (J) diastolic [Ca2+]SR, (K) systolic [Ca2+]SR, and (L) [Ca2+]SR amplitude at 1, 2 and 3 Hz pacing.

FIGURE 3. Effects of modulating the SR Ca2+ leak flux, Jleak, on Vm, [Ca2+]i, and [Ca2+]SR. (A) Example action potentials for 50% and 200% Kleak at 1 Hz pacing. Sensitivity analyses of modulating Kleak on measurements of (B) resting Vm, (C) maximum Vm, and (D) time to 90% repolarization at 1, 2 and 3 Hz pacing. (E) Example [Ca2+]i transients for 50% and 200% Kleak at 1 Hz pacing. Sensitivity analyses of modulating Kleak on measurements of (F) diastolic [Ca2+]i, (G) systolic [Ca2+]i, and (H) [Ca2+]i amplitude at 1, 2 and 3 Hz pacing. (I) Example [Ca2+]SR transients for 50% and 200% Kleak at 1 Hz pacing. Sensitivity analyses of modulating Kleak on measurements of (J) diastolic [Ca2+]SR, (K) systolic [Ca2+]SR, and (L) [Ca2+]SR amplitude at 1, 2 and 3 Hz pacing.

FIGURE 4. Summary of effects of modulating Gbkg or Kleak independently on Vm. Sensitivity analyses of modulating Gbkg on measurements of (A) resting Vm, (B) maximum Vm, and (C) time to 90% repolarization normalized by the default model parameters. Sensitivity analyses of modulating Kleak on measurements of (D) resting Vm, (E) maximum Vm, and (F) time to 90% repolarization normalized by the default model parameters. Summary of the (G) quadratic term, (H) linear term and (I) constant term calculated by quadratic polynomial fits to the normalized sensitivity analyses in (A–H).

FIGURE 5. Summary of effects of modulating Gbkg or Kleak independently on [Ca2+]i. Sensitivity analyses of modulating Gbkg on measurements of (A) diastolic [Ca2+]i, (B) systolic [Ca2+]i, and (C) [Ca2+]i amplitude normalized by the default model parameters. Sensitivity analyses of modulating Kleak on measurements of (D) diastolic [Ca2+]i, (E) systolic [Ca2+]i, and (F) [Ca2+]i amplitude normalized by the default model parameters. Summary of the (G) quadratic term, (H) linear term and (I) constant term calculated by quadratic polynomial fits to the normalized sensitivity analyses in (A–H).

FIGURE 6. Summary of effects of modulating Gbkg or Kleak independently on [Ca2+]SR. Sensitivity analyses of modulating Gbkg on measurements of (A) diastolic [Ca2+]SR, (B) systolic [Ca2+]SR, and (C) [Ca2+]SR amplitude normalized by the default model parameters. Sensitivity analyses of modulating Kleak on measurements of (D) diastolic [Ca2+]SR, (E) systolic [Ca2+]SR, and (F) [Ca2+]SR amplitude normalized by the default model parameters. Summary of the (G) quadratic term, (H) linear term and (I) constant term calculated by quadratic polynomial fits the normalized sensitivity analyses in (A–H).

FIGURE 7. Dual-parameter sensitivity analysis of modulating Gbkg and Kleak at 1 Hz pacing. Surface plots with contour lines for measurements of (A) resting Vm, (B) maximum Vm, (C) APD90, (D) diastolic [Ca2+]i, (E) systolic [Ca2+]i, (F) [Ca2+]i amplitude, (G) diastolic [Ca2+]SR, (H) systolic [Ca2+]SR, and (I) [Ca2+]SR amplitude.

FIGURE 8. Example Ca2+ transients of balanced background Ca2+ entry and SR Ca2+ leak. (A) 200% Gbkg and 270% Kleak balance their opposing modulations on systolic [Ca2+]i while increasing diastolic [Ca2+]i by 7.9%. (B) Zoomed-in region demonstrating 7.9% increase in diastolic [Ca2+]i from default values (black line). (C) 200% Gbkg and 270% Kleak balance opposing effects on SR load.